Bidirectional Associations Between Circulating Polyunsaturated Fatty Acids and Female Reproductive Endocrine-Related Diseases: A Mendelian Randomization Study

OBJECTIVE: Polyunsaturated fatty acids (PUFAs) are hypothesized to modulate female reproductive endocrine disorders, yet their causal relationships remain elusive. We employed Mendelian randomization (MR) to investigate bidirectional causality between circulating PUFAs (omega-3/6 subtypes, docosahexaenoic acid [DHA], linoleic acid) and endometriosis, infertility, polycystic ovary syndrome (PCOS), premenstrual syndrome, and premature ovarian insufficiency (POI). MATERIALS AND METHODS: In this two-sample MR study, exposure data from a GWAS of 115,006 Europeans were analyzed against outcome data (FinnGen and other large-scale GWAS). Forward MR assessed PUFA effects on disorders; reverse MR evaluated disorder-driven PUFA alterations. Sensitivity analyses (MR-Egger, MR-PRESSO, leave-one-out) ensured robustness. RESULTS: Elevated linoleic acid and total omega-6 levels increased endometriosis (OR=1.127, P=0.039; OR=1.123, P=0.037) and infertility risks (OR=1.155, P=0.019), while higher PUFA-to-total fatty acid ratios conferred protection (endometriosis: OR=0.857, P=0.017). PCOS genetically reduced DHA and total omega-3 levels while elevating omega-6/3 ratios (P<0.05). No reverse effects were observed for other disorders. CONCLUSION: Our findings implicate linoleic acid and omega-6 PUFAs as potential risk factors for endometriosis and infertility, whereas balanced PUFA ratios may be protective. PCOS disrupts omega-3 homeostasis, suggesting bidirectional metabolic interplay. These results highlight PUFAs as modifiable targets for nutritional and therapeutic strategies in reproductive health, warranting further mechanistic and clinical validation.